This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Existing treatments for major depressive disorder (MDD) generally take weeks to months to exert their maximal benefit. Given the morbidity and mortality resulting from failure to treat depressive symptoms in a timely fashion, there is an urgent need to develop rapidly-acting treatments, as well as to identify optimal continuation treatment approaches. Ketamine, a high-affinity NMDA glutamate receptor antagonist, has been used as a standard intravenous (IV) anesthetic agent for many years in both pediatric and adult patients, with doses as high as 2 mg/kg. Beyond its well-established role in anesthesia and pain management, there is emerging evidence that ketamine may have rapid antidepressant properties for patients with severe mood disorders. Indeed, a recent placebo-controlled investigation replicated an earlier pilot study (Berman et al., 2000) and showed a robust acute antidepressant effect of a single dose of ketamine (0.5 mg/kg) in patients with treatment-resistant unipolar depression (Zarate et al., 2006), with many patients maintaining a mood improvement for several days. In order to fully capitalize on the therapeutic promise of IV ketamine for treatment resistant depression (TRD), two new issues will be addressed in this present study. First, it is important to identify the effectiveness of repeated doses of IV ketamine, in order to possibly prolong the antidepressant response beyond the acute effect of each individual administration. Second, it is crucial to identify the maximally effective while minimally aversive dose of IV ketamine that can be safely administered to outpatients over repeated doses. Patient acceptability of the drug regimen is key in ensuring the possible sustained benefit of IV ketamine. A final question pertains to the effect of ketamine treatment (both single and repeated dosing) on brain activity. We are adding functional imaging to this protocol in order to investigate (1) treatment-induced changes in task-related BOLD responses measured using functional magnetic resonance imaging (fMRI) and (2) treatment-induced changes in resting-state connectivity measured using functional connectivity MRI (fcMRI). This research protocol will test the efficacy of repeated IV ketamine administration in 20 patients with treatment-resistant MDD who exhibit an acute response to a single dose of IV ketamine. The dose to be used for repeated administration will be determined using the single-dose response. The main outcome measure is time to relapse following the antidepressant response to repeated dosing.